Structure-activity relationship (SAR) investigations of substituted imidazole analogs as TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.08.044

A novel series of 4,5-biarylimidazoles as TRPV1 antagonists were designed based on the previously reported 4,6-disubstituted benzimidazole series. The analogs were evaluated for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. These studies led to the identification of a highly potent and orally bioavailable TRPV1 antagonist, imidazole 33.

Full text of DOI:10.1016/j.bmcl.2007.08.044

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5825–5830
Structure–activity relationship (SAR) investigations of substituted
imidazole analogs as TRPV1 antagonists
Vijay K. Gore,a,* Vu V. Ma,a Rami Tamir,b Narender R. Gavva,b
James J. S. Treanorb and Mark H. Normana
aChemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
bDepartment of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Received 29 May 2007; revised 19 August 2007; accepted 21 August 2007
Available online 25 August 2007
Abstract—A novel series of 4,5-biarylimidazoles as TRPV1 antagonists were designed based on the previously reported 4,6-disub-
stituted benzimidazole series. The analogs were evaluated for their ability to block capsaicin- or acid-induced calcium influx in
TRPV1-expressing CHO cells. These studies led to the identification of a highly potent and orally bioavailable TRPV1 antagonist,
imidazole 33.
Ó 2007 Elsevier Ltd. All rights reserved.
Vanilloid receptor-1 (VR1 or TRPV1) is a member of
the transient receptor potential (TRP) family of ion
channels.1 This highly Ca2+ permeable receptor is pre-
dominantly expressed in peripheral sensory neurons that
are involved in nociception and neurogenic inflamma-
tion.2 TRPV1 is activated by endogenous ligands such
as anandamide and lipoxygenase metabolites.3,4 It is
also activated by a variety of stimuli such as heat and
acid, and exogenous chemical stimuli such as capsaicin
(the pungent component found in chili peppers). TRPV1
activation with agonists is known to have analgesic ef-
fects because it leads to desensitization of sensory neu-
rons, making them less sensitive to painful stimuli.
However, prolonged use of such agonists (e.g., topical
muscle pain relievers containing capsaicin as the active
component) is associated with side effects such as burn-
ing sensation, irritation, and neurotoxicity due to con-
tinuous influx of Ca2+ ions into the cells.5 TRPV1
receptor antagonists on the other hand inhibit the acti-
vation of the primary sensory neurons and therefore
may have fewer side effects than TRPV1 agonists.6 This
hypothesis is also supported by the observation that
thermal hyperalgesia is reduced in inflammatory pain
models in knockout mice lacking the TRPV1 gene.7
In our work toward the discovery of new analgesic
agents, we recently reported the synthesis and SAR
studies of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-
1H-benzo-[d]imidazoles as potent TRPV1 antagonists
(exemplified by compound 1).8 During the course of
this work we identified a hydrophobic binding pocket
in the TRPV1 receptor which could be accessed from
the C-4 position of the benzimidazole ring. We found
that significant enhancements in TRPV1 potency
could be obtained by the addition of hydrophobic
groups in this C-4 position. As an alternative way
to gain entry into this binding pocket we designed a
series of novel trisubstituted imidazole analogs (e.g.,
compound 2). In this series, the imidazole ring would
be shifted slightly (compared to the 4-substituted
benzimidazole ring) to position the aromatic substitu-
ents at C-4 and C-5 in the optimal region of the
space. Superposition of the molecules in this way sug-
gested that the 4,5-biaryl-substituted imidazole 2
would overlap well with the 4,6-disubstituted benz-
imidazole analog 1 (Fig. 1).
To test this hypothesis we prepared imidazole 2 and
evaluated its ability to inhibit the TRPV1 receptor. We
found that compound 2 and hence the 4,5-disubsti-
tuted-imidazole group could serve as an alternative to
the C-4-substituted benzimidazole scaffold (1). Herein,
we describe the synthesis and biological activity of a ser-
ies of 4,5-biaryl-substituted imidazoles of type 2 as a no-
vel class of TRPV1 antagonists.
Keywords: VRI; TRPV1; Vanilloid receptor-1; Biaryl imidazoles;
TRPV1 antagonists.
*
Corresponding author. Tel.: +1 805 447 4823; fax: +1 805 480
1337; e-mail: vgore@amgen.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.08.044

5826
V. K. Gore et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5825–5830
R3
R3
N
NH
a, b
R1
N
NH
R1
N
.
HCl
NH2
9: R1 = 3'-trifluoromethylpyridine, R3 = H
10: R1 = 3'-trifluoromethylpyridine, R3 = (R)-Me
11: R1 = Cbz, R3 = H
8
12: R1 = Cbz, R3 = (R)-Me
Scheme 2. Synthesis of guanidines 9–12. Reagents and conditions: (a)
1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea, Et3N, HgCl2,
CH2Cl2, room temperature, 12 h; (b) 4 N HCl, 1,4-dioxane, room
temperature, 8 h, 60% (over two steps).
Scheme 3 details the syntheses of the intermediate 1,2-
biarylethane-1,2-diones. Biarylethane-diones (14–19)
were obtained in good yields by Cu(I)-mediated cross-
coupling of various substituted benzoyl chlorides with
the appropriately substituted benzylzinc(II) bromides,
followed by treatment with n-bromosuccinimide
(NBS).11,12
Figure 1. Superimposition of compounds
1 (blue) and 2 (red).
aInhibition of capsaicin-mediated 45Ca2+ influx in CHO cells express-
ing rat TRPV1 receptor. bInhibition of acid-mediated (pH 5) 45Ca2+
influx in CHO cells expressing rat TRPV1 receptor.
General method A was followed for synthesis of the 4,5-
biarylimidazoles 2 and 21–27 as shown in Scheme 4. The
reaction of biaryl-diones 14–19 and commercially avail-
able propane-1,2-dione 20 with guanidines 9 and 10 in
presence of Hunig’s base followed by catalytic hydroge-
nation provided the final products 2 and 21–27.
For the purposes of our study, we utilized the rat
TRPV1 channel recombinantly expressed in Chinese
hamster ovary (CHO) cells. The compound’s ability to
inhibit both the capsaicin- and acid-mediated influx of
45Ca2+ was examined. Our goal was to improve potency
and pharmacokinetic properties over compound 2 as
well as to gain better understanding of the pharmaco-
phores required for TRPV1 activity in this novel series.
Guanidines 11 and 12 were reacted with the diones 14
and 17 in presence of Hunig’s base, followed by hydro-
genolysis to yield the intermediates 28–30 (Scheme 5).
These intermediates were elaborated using method B de-
scribed earlier to synthesize the final products 31–33.
Accordingly, compounds 28–30 were coupled with
SEM-protected (2,3-dichloropyridin-5-yl)methanol un-
der microwave-assisted conditions, followed by treat-
ment with trifluoroacetic acid to yield the final
products 31–33 (Scheme 5).
The majority of compounds required for our SAR study
were prepared by one of two general routes (methods A
and B, Scheme 1). In method A, 4,5-biarylimidazoles 3
were obtained by coupling piperazinyl-guanidines 4 with
1,2-biarylethane-1,2-diones 5 in the presence of Hunig’s
base followed by hydrogenolysis.9 In method B, the final
products 3 were obtained by coupling chloro-pyridine
derivatives (6) with 2-piperazinyl-4,5-biarylimidazoles
(7) by heating under microwave-assisted conditions in
the presence of base.
The analog without a substituent at the C-4 position of
the imidazole ring (i.e., compound 37) was synthesized
as shown in Scheme 6. Amino-aryl-ethanone hydrochlo-
ride 34 was converted to the corresponding 4-substi-
tuted-1H-imidazol-2(3H)-one 35.13 The imidazolone
was treated with phosphorus oxychloride followed by
protection with a SEM-group to yield the N-1-protected
2-chloroimidazole 36. This intermediate was subjected
to Pd-mediated amination14 reaction conditions with
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine followed
The requisite piperazinyl-guanidines (9–12) were synthe-
sized in a two-step sequence as shown in Scheme 2.
Treatment of various piperazines (8) with 1,3-bis(tert-
butoxycarbonyl)-2-methyl-2-thiopseudourea in the pres-
ence of a mercury(II) salt promoter and triethylamine as
the base resulted in formation of the bis-Boc-protected
guanidines, which, upon deprotection using 4 N HCl
in dioxane, yielded the free guanidines (9–12).10
O
O
R4
R5
a, b
R4
ZnBr
R3
R4
O
O
NH
N
R1
N
N
+
14: R4 = Ph, R5 = 4-CF3Ph
13
R5
NH2
15: R4 = Ph, R5 = 3-CF3Ph
A
B
R2
R3
N
16: R4 = R5 = 4-CF3Ph
4
5
R4
R5
17: R4 = 3,4,5-trifluorophenyl, R5 = 4-CF3Ph
18: R4 = 3,5-difluorophenyl, R5 = 4-CF3Ph
19: R4 = R5 = 3,4,5-trifluorophenyl
N
N
R1
N
N
H
R3
N
R2
R4
R5
N
N
3
R1
Cl
+
HN
Scheme 3. Synthesis of 1,2-biarylethane-1,2-diones 14–19. Reagents
and conditions: (a) benzoyl chloride, THF, LiBr, CuCN, ꢀ25 °C to
room temperature, 16 h; (b) NBS, DMSO, 65 °C, 4 h, 35% (over two
steps).
N
R2
H
6
7
Scheme 1. Retrosynthesis of 4,5-biarylimidazoles (3).

V. K. Gore et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5825–5830
5827
R3
N
R3
N
R4
R5
R4
R5
O
O
NH
a, b
N
N
N
.
HCl
NH2
+
N
N
N
H
CF3
CF3
2: R3 = H, R4 = Ph, R5 = 4-CF3Ph
9,10
14-20
21: R3 = H, R4 = Ph, R5 = 3-CF3Ph
22: R3 = H, R4 = R5 = 4-CF3Ph
23: R3 = H, R4 = 3,4,5-trifluorophenyl, R5 = 4-CF3Ph
24: R3 = H, R4 = 3,5-difluorophenyl, R5 = 4-CF3Ph
25: R3 = H, R4 = R5 = 3,4,5-trifluorophenyl
26: R3 = (R)-Me, R4 = Ph, R5 = 4-CF3Ph
27: R3 = H, R4 = Me, R5 = 4-CF3Ph
Scheme 4. Synthesis of compounds 2 and 21–27. Reagents and conditions: (a) 14–19, MeOH, DIPEA, room temperature, 8 h; (b) MeOH, 10% Pd/C,
H2, room temperature, 12 h, 30% (over two steps).
R3
R4
O
O
NH
a, b
.
+
HCl
NH2
Cbz N
N
CF3
14,17
11,12
R4
R3
N
R3
R4
N
N
c, d
N
N
Cl
HN
N
N
H
HO
N
H
CF3
CF3
28: R3 = H, R4 = Ph
29: R3 = (R)-Me, R4 = Ph
30: R3 = (R)-Me, R4 = 3,4,5-trifluorophenyl
31: R3 = H, R4 = Ph
32: R3 = (R)-Me, R4 = Ph
33: R3 = (R)-Me, R4 = 3,4,5-trifluorophenyl
Scheme 5. Synthesis of compounds 31–33. Reagents and conditions: (a) 14 or 17, EtOH, DIPEA, room temperature, 5 h; (b) EtOH, 20% Pd(OH)2/C,
H2, room temperature, 6 h, 40% (over two steps); (c) 2,3-dichloro-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)pyridine, NMP, NaHCO3,
Microwave, 190 °C, 0.5 h, 65–70%; (d) TFA, room temperature, 2 h, 65%.
H
.
Scheme 8 shows the preparation of ester analog 43.
Methyl 1H-imidazole-4-carboxylate (41) was subjected
to bromination conditions followed by protection with
a SEM-group. Subsequent treatment with 1-(3-(trifluo-
romethyl)pyridin-2-yl)piperazine under microwave-as-
F3C
HCl
NH2
a
b, c
N
O
N
N
H
O
CF3
34
35
sisted
conditions
provided
intermediate
42.
N
d,e
N
N
Intermediate 42 was subjected to deprotection using
trifluoroacetic acid followed by Suzuki coupling with
(4-trifluoromethyl)phenylboronic acid to obtain ester
analog 43.
Cl
N
N
N
H
CF3
SEM
CF3
CF3
36
37
Scheme 6. Synthesis of compound 37. Reagents and conditions:
(a) KOCN, H2O, 80 °C, 4 h, 85%; (b) POCl3, 110 °C, 12 h, 90%;
(c) ClCH2OCH2CH2SiMe3 (SEM-Cl), DIPEA, CH2Cl2, 12 h, 90%;
(d) 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine, Pd(dba)3, 2-(di-tert-
butylphosphino)biphenyl, NaOtBu, microwave, 150 °C, 10 min, 15%;
(e) TFA, CH2Cl2, room temperature, 5 h, 70%.
The syntheses of the final four amide derivatives 45–48
are shown in Scheme 9. The Suzuki coupling of 42 with
4-(trifluoromethyl)phenylboronic acid followed by
hydrolysis with LiOH provided carboxylic acid 44.
Compound 44 was condensed with various amines15 un-
der peptide coupling conditions in presence of BOP re-
agent and the intermediates were deprotected using
trifluoroacetic acid to obtain amide analogs 45–48.
by deprotection using trifluoroacetic acid to obtain ana-
log 37.
The compounds were tested for their ability to block the
capsaicin- or acid-induced (pH 5) uptake of 45Ca2+ in
CHO cells expressing rat TRPV1. Functional activity
is reported as IC50 (nM) and represents the average of
at least two independent experiments with three repli-
cates at each concentration.
The 5-chloro substituted analog 40 was synthesized in
four steps starting from 2-bromo-4,5-dichloro-1H-imid-
azole as shown in Scheme 7. Bromo-imidazole 38 was
treated with SEM-Cl followed by treatment with 1-(3-(tri-
fluoromethyl)pyridin-2-yl)piperazine under microwave-
assisted conditions to yield intermediate 39.
Intermediate 39 was subjected to Suzuki coupling with
(4-trifluoromethyl)phenylboronic acid followed by
deprotection using trifluoroacetic acid to obtain analog
40.
We first examined the substitutions of the imidazole ring
(R4 and R5, Tables 1 and 2 ). The imidazole analog 2
had an IC50 value of 107 nM in the capsaicin-mediated

5828
V. K. Gore et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5825–5830
Cl a, b
Cl
Cl
Cl
c, d
Cl
N
N
N
N
N
N
Br
N
N
N
N
N
H
N
H
CF3
CF3
SEM
39
CF3
38
40
Scheme 7. Synthesis of compound 40. Reagents and conditions: (a) ClCH2OCH2CH2SiMe3, NaH, THF, 0.5 h, 65%; (b) 1-(3-(trifluoromethyl)pyri-
din-2-yl)piperazine, microwave, 130 °C, 15 min, 6%; (c) (4-trifluoromethyl)phenylboronic acid, PdCl2(PPh3)2, Na2CO3, DME/H2O/EtOH (7:3:2),
microwave, 130 °C, 1 h; (d) TFA, CH2Cl2, room temperature, 1 h, 3% (over two steps).
O
O
O
a, b, c
d, e
N
N
N
N
N
N
O
O
O
N
N
N
N
N
H
N
H
Br
CF3
CF3
SEM
CF3
41
42
43
Scheme 8. Synthesis of compound 43. Reagents and conditions: (a) Br2, AcOH, 12 h, room temperature, 15%; (b) ClCH2OCH2CH2SiMe3, NaH,
THF, 12 h, 90%; (c) 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine, microwave, 130 °C, 15 min, 55%; (d) TFA, room temperature, 1 h, 75%; (e) (4-
trifluoromethyl)phenylboronic acid, PdCl2(PPh3)2, Na2CO3, DME/H2O/EtOH (7:3:2), microwave, 130 °C, 1 h, 15%.
O
R4
a, b
c, d
N
N
N
N
OH
N
N
N
N
42
N
H
N
H
CF3
CF3
CF3
CF3
44
45-48
Scheme 9. Synthesis of compounds 45–48. Reagents and conditions: (a) (4-trifluoromethyl)phenylboronic acid, Pd(PPh3)4, Na2CO3, 1,4-dioxane,
microwave, 130 °C, 15 min, 85%; (b) LiOH, THF/H2O (5:1), 0 °C to room temperature, 16 h, 55%; (c) Amine, BOP, DIPEA, CH2Cl2, room
temperature, 48 h; (d) TFA, room temperature, 1 h, 16% (over two steps).
Table 1. Structures and assay results of analogs 2, 37, 27, 40 and 43,
and 45–48
cin-mediated assay (IC50 = 861 nM) compared to com-
pound 2, and was inactive in the acid-mediated assay
(Table 1). This result indicated that 4,5-disubstitution
R4
N
N
of the imidazole ring was essential for activity in both
cell assays. Next, we tested compounds 27, 40, and 43
containing smaller groups such as methyl, chlorine,
and methyl ester at the C-4 position, respectively. All
three analogs were moderately active in the capsaicin-
mediated assay; however the methyl ester 43 was the
only analog that showed activity in both cell assays.
These data suggested that larger substitutents were pre-
ferred at the C-4 position of the imidazole ring and
could provide potency enhancement in both assays.
Therefore, we utilized methyl ester 43 to prepare amide
analogs 45–48 (Table 1). Basic amines such as pipera-
zine, piperidine, and pyrrolidine were introduced in an
attempt to improve the solubility properties. Unfortu-
nately, all four amides 45–48 demonstrated weak activ-
ity in both capsaicin and acid-mediated cell assays.
N
N
N
H
CF3
CF3
Compound R4
rTRPVI (Cap)a rTRPVI (pH 5)a
IC50 SEM (nM) IC50 SEM (nM)
2
37
27
40
43
Ph
107 21
861 74
628 71
216 30
>4000
>4000
H
Me
Cl
COOMe
160 28
1170 1650
>4000
180 32
O
N
45
700 308
1000 84
>4000
N
O
46
1900 700
N
N
H
Because the amide modifications did not provide any
potency enhancement, we explored various 4,5-biaryl
modifications on the imidazole ring (Table 2). Accord-
ingly, replacement of the p-(trifluoromethyl)phenyl
group of compound 2 with the corresponding meta-
substituted analog (21) maintained potency in the acid-
mediated assay but was 10- to 12-fold weaker in the cap-
saicin-mediated assay (Table 2). These results suggested
that an aryl substitution with p-(trifluoromethyl)phenyl
group was optimal for activity, therefore we retained it
as the R5 substituent and investigated additional substi-
tutions on the R4 position of the imidazole ring. Com-
pounds 22–24 were tested for functional activity and
analog 23 with the 3,4,5-trifluorophenyl substitution
H
N
O
47
48
2950 72
>4000
N
H
O
N
4100 1100
3300 1200
N
H
a The inhibition assays were carried out in rat TRPV1 channel
expressed in CHO cells. Results are the average of at least two
independent experiments with three replicates at each concentration.
assay and 216 nM in the acid-mediated assay. Removal
of the phenyl group from the imidazole ring resulted in
compound 37, which had weaker potency in the capsai-

V. K. Gore et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5825–5830
Table 2. Structures and assay results of analogs 2 and 21–25
5829
R4
R5
N
N
N
N
N
H
CF3
Compound
R4
R5
rTRPVI (Cap)a IC50 SEM (nM)
rTRPVI (pH 5)a IC50 SEM (nM)
2
21
22
23
24
25
Ph
Ph
4-CF3Ph
3-CF3Ph
107 21
1235 265
573 31
216 30
165 17
146 84
4-CF3Ph
4-CF3Ph
4-CF3Ph
3,4,5-Trifluoro-Ph
3,5-Difluoro-Ph
3,4,5-Trifluoro-Ph
7
35
44
2
4
4
20
85 10
32
3
4-CF3Ph
3,4,5-Trifluoro-Ph
3
a The inhibition assays were carried out in rat TRPV1 channel expressed in CHO cells. Results are the average of at least two independent
experiments with three replicates at each concentration.
showed a 15-fold enhancement in potency in the capsa-
icin-mediated assay and a 10-fold improvement in the
acid-mediated assay as compared to compound 2. How-
ever, compound 25 with the 4,5-bis(3,4,5-trifluorophe-
nyl) substitution on the imidazole ring did not show
further improvement in the cell potency. These data
indicated that the 4,5-biaryl substitution in analog 23
was the optimal combination of substituents in this
series.
the cell assays. Each of these modifications individually
did not provide the potency enhancement in the cell as-
says; however, when we introduced these two modifica-
tions in the same molecule, the resulting analog 32
showed a 4- to 5-fold improvement in potency in both
assays (Table 3). This finding was consistent with obser-
vations in our previously reported benzimidazole work.8
In the final phase of this investigation we evaluated the
effect of combining the structural features of the two
most potent analogs (compounds 23 and 32). For exam-
ple, we retained the 4,5-biarylimidazole substitution
from 23 and combined it with the pyridyl-piperazine
unit from 32 (Table 4). This hybrid analog (33) was
more potent in both the capsaicin-mediated and acid-
mediated cell assays compared to analogs 23 or 32.
In the next phase of our investigation, we explored the
effects of modifications on the pyridyl-piperazine moiety
of compound 2 (Table 3). Based on our SAR under-
standing of the benzimidazole series we introduced the
(R)-2-methylpiperazine and the 30-chloro-50-hydroxy-
methyl pyridine ring modifications in this new series.
Accordingly, compounds 26 and 31, formed by intro-
duction of the (R)-2-methylpiperazine and 30-chloro-50-
hydroxymethyl pyridine, respectively, were tested in
Because of their excellent in vitro potencies, we studied
compounds 23 and 33 in more detail. The pharmacoki-
netic (PK) profiles with intravenous (iv) dosing in Spra-
gue–Dawley rats for compounds 23, 33, and the initial
hit 2, are shown in Table 5. A high rate of clearance
(CL) was observed for compound 2 (10.0 L/h/kg) follow-
ing iv dosing; however, compounds 23 and 33 exhibited
relatively low rates of clearance (1.9 and 0.8 L/h/kg,
respectively). Although the rate of clearance for com-
pound 23 was lower than that for compound 2, the vol-
ume of distribution was also lower (Vss = 1.7 L/kg),
consequently no improvement in half-life relative to com-
pound 2 was observed. In contrast, compound 33 demon-
strated low clearance (0.8 L/h/kg), combined with a high
volume of distribution (5.4 L/kg), resulting in an overall
increase in half-life over compound 2 (6.3 vs 2.3 h).
Table 3. Structures and assay results of analogs 2, 26, 31, and 32
N
X
N
H
CF3
Compound X
rTRPVI (Cap)a rTRPVI
IC50 SEM
(nM)
(pH 5)a IC50
SEM (nM)
N
N
N
N
2
107 21
216 30
CF3
The results from PK studies in rats dosed orally (po)
with suspensions of compounds 2, 23, and 33 are sum-
marized in Table 6. While the oral bioavailability of
compounds 2 and 23 was low (Foral = 6% and 3%,
respectively), compound 33 was well absorbed with a
bioavailability of 40%. The maximum plasma concen-
tration (Cmax) following po dose for compound 33 was
347 ng/mL at 4.7 h, which was significant improvement
over compounds 2 (Cmax = 13 ng/mL at 1.3 h) and 23
(Cmax = 17 ng/mL at 1.0 h).
N
N
26
31
117
5
341 29
160 22
CF3
N
N
N
N
N
90 19
HO
Cl
N
32
26
3
29
2
HO
Cl
a The inhibition assays were carried out in rat TRPV1 channel
expressed in CHO cells. Results are the average of at least two
independent experiments with three replicates at each concentration.
In conclusion, through SAR studies based on compound
2, we identified a novel class of imidazole analogs as

5830
V. K. Gore et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5825–5830
Table 4. Structures and assay results of analogs 23, 32, and 33
R3
N
R4
N
N
R1
N
N
R2
H
CF3
rTRPVI (Cap)a IC50 SEM (nM)
Compound
R1
R2
R3
R4
rTRPVI (pH 5)a IC50 SEM (nM)
23
32
33
H
CF3
Cl
H
3,4,5-Trifluoro
Ph
3,4,5-Trifluoro
7
26
1
2
20
29
4
3
CH2OH
CH2OH
(R)-Me
(R)-Me
3
0.4
2
0.4
Cl
a The inhibition assays were carried out in rat TRPV1 channel expressed in CHO cells. Results are the average of atleast two independent experiments
with three replicates at each concentration.
References and notes
1. Vanilloid receptor-1 is referred to as TRPV1 in this report
according to the recently adopted nomenclature: Montell,
Table 5. Mean pharmacokinetic parameters following intravenous
dosea in Sprague–Dawley ratsb of compounds 2, 23, and 33
C.; Birnbaumer, L.; Flockerzi, V.; Bindels, R. J.; Bruford,
E. A.; Caterina, M. J.; Clapham, D. E.; Harteneck, C.;
Heler, S.; Julius, D.; Kojima, I.; Mori, Y.; Penner, R.;
Prawitt, D.; Scharenberg, A. M.; Schultz, G.; Shimizu, N.;
Zhu, M. X. Mol. Cell 2002, 9, 229.
Compound
AUC0ꢀinf
(ng h/mL)
CL (L/h/kg)
t1/2 (h)
Vss (L/kg)
2
23
33
105
529
10.0
1.9
2.3
1.9
6.3
5.0
1.7
5.4
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1233
0.8
a Dosed at 1 mg/kg as a solution in DMSO.
b n = 3 animals per study.
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Table 6. Mean pharmacokinetic parameters following oral dosea in
Sprague–Dawley ratsb of compounds 2, 23, and 33
Compound Cmax
tmax AUC0ꢀinf Bioavailability F(%)
(ng/mL) (h)
(ng h/mL)
2
23
33c
13
17
1.3
1.0
4.7
30
80
6
3
347
2456
40
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a Dosed at 5 mg/kg as a suspension in 5% Tween 80 in Oraplus.
b n = 2 animals per study.
c n = 3 animals per study.
potent and orally bioavailable TRPV1 antagonists. Dis-
covery of analogs 23 and 33 supported our hypothesis
that the 4,5-biarylimidazole core could serve as an alter-
native to the previously disclosed benzimidazole core.8
We were able to achieve 100-fold improvement in the
capsaicin-mediated assay and 50-fold improvement in
the acid-mediated cell assay compared to the initial com-
pound 2. In addition, we found that 30-chloro-50-
hydroxymethylpyridine substitution on the (R)-2-meth-
ylpiperazine ring resulted in the most potent analog
33, which also had a significantly improved pharmacoki-
netic profile over compounds 2 and 23.
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Acknowledgments
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We thank our colleagues Vellarkad N. Viswanadhan,
Sekhar Surapaneni, Annette Bak, and their co-workers
in the molecular structure, PKDM, and pharmaceutics
departments, respectively. We also acknowledge Randy
Hungate, Paul J. Reider, H. Christian Fibiger, and Jean-
Claude Louis for their support.
15. Balan, C.; Bo, Y.; Dominguez, C.; Fotsch, C.; Gore, V. K.;
Ma, V. V.; Norman, M. H.; Ognyanov, V. I.; Qian, Y.;
Wang, X.; Xi, N.; Xu, S. Benzimidazole derivatives and
their use as vanilloid receptor ligands. WO 04035549-A1,
2004.